• Users Online: 275
  • Print this page
  • Email this page

Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 87-94

Patients with critical limb ischemia (CLI) not suitable for revascularization: the “dark side” of CLI

Department of Vascular Surgery, Unit of Angiology, Ospedale San Martino Belluno, AULSS 1 Dolomiti, Belluno, Italy

Date of Submission08-Apr-2021
Date of Decision01-May-2021
Date of Acceptance03-May-2021
Date of Web Publication20-Jul-2021

Correspondence Address:
Dr. Romeo Martini
Unit of Angiology, Ospedale San Martino Belluno, AULSS 1 Dolomiti, Belluno
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2589-9686.321924

Rights and Permissions

Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease (PAD). Its prognosis is poor, with high rates of limb amputation and cardiovascular mortality. The international guidelines consider limb revascularization as the first line of the treatment strategy for CLI. However, despite the progress of revascularization techniques, many patients with CLI are still considered not suitable for these procedures and treated with conservative limb treatments. We have consulted the most important guidelines on PAD and CLI published over the past two decades focusing on the epidemiology, treatment, and outcomes of CLI patients not suitable for revascularization. Our review shows that only the TASC guidelines report 25% of CLI patients conservatively treated. Regarding the treatments, all the guidelines agree that the conservative treatment is based on the best medical management of cardiovascular risk factors associated with pain drugs and wound management. Other treatments such as prostanoids, spinal cord stimulation, vasodilators, or angiogenic therapies have shown uncertain positive outcomes in reducing limb amputation and mortality. In conclusion, this work outlines the scarce consideration that the guidelines have had about these patients over the past two decades. However, this review tries to draw the main novelties and possible future treatments for the better management of this group of patients still resident in the “dark side” of the CLI.

Keywords: Conservative treatment, critical limb ischemia, critical limb threatening ischemia

How to cite this article:
Martini R, Ghirardini F. Patients with critical limb ischemia (CLI) not suitable for revascularization: the “dark side” of CLI. Vasc Invest Ther 2021;4:87-94

How to cite this URL:
Martini R, Ghirardini F. Patients with critical limb ischemia (CLI) not suitable for revascularization: the “dark side” of CLI. Vasc Invest Ther [serial online] 2021 [cited 2021 Dec 8];4:87-94. Available from: https://www.vitonline.org/text.asp?2021/4/3/87/321924

  Introduction Top

Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease (PAD), clinically defined as limb rest pain with or without foot or leg skin ulcers or gangrene.[1]

CLI is associated with macro and microcirculatory disorders[2] with high limb amputation rates and cardiovascular mortality.[3]

The international guidelines consider that limb revascularization is the first-choice treatment for CLI patients.[4],[5] However, in the past two decades, despite the progress of the revascularization procedures, particularly of endovascular techniques, many patients with CLI are still considered not suitable for revascularization.[5]

These patients are a heterogeneous group, often elderly and frail subjects, with multiple comorbidity factors such as diabetes, chronic kidney disease, and chronic pulmonary disease. Frequently, they have previously failed limb revascularization procedures with a poor leg-pedal arterial run-off, but their limb is still viable and not indicated for primary amputation.[6] Wounds and conservative limb medical therapy consisting of pain control wound treatments with the best cardiovascular risk management is their therapeutic option in real life.[7]

Prostanoids,[8],[9], [10,[11] spinal cord stimulation,[12] intermittent pneumatic compression,[13],[14],[15],[16],[17] and angiogenic treatment[18],[19],[20] over the past two decades have been utilized to improve the CLI limb and patients' survival. However, the outcomes achieved with these treatments did not show significant improvements. Therefore, over the past two decades, the guidelines have gradually expressed weak recommendations on their use, leaving these patients orphans of specific treatments.[1],[3],[4],[5],[7],[10],[21],[22],[23],[24],[25]

In contrast with this scenario, some authors have recently hypothesized that the new cardiovascular management strategy as the statin treatment changes may have determined better limb amputation and mortality rates over the past 10 years.[26],[27]

Moreover, to these hopeful suggestions, the reduction of major amputations and mortality observed in PAD patients treated with a low dose of direct oral anticoagulant and with inhibitors of proprotein convertase subtilisin/kexin type could also positively affect CLI patients.[28],[29]

Therefore, there are now compelling arguments for reviewing some issues regarding the patients and drawing new suggestions about their treatments. This paper hopes to help stimulate future investigation about these neglected patients' residents in the “dark side” of the CLI.

Epidemiology of patients with critical limb ischemia not suitable for revascularization

There is scarce evidence in the most consulted guidelines on PAD about the epidemiology of patients with CLI not suitable for revascularization.

In 2000 and 2007, the TASCs reported that 50% of patients at their first CLI episode had been treated with revascularization procedures. Of the remaining patients considered unsuitable for revascularization, 25% were treated with primary amputations and 25% with conservative limb treatment, consisting basically in medical therapy.[1],[10]

In the past two decades, no other guidelines have reported the rate of CLI patients considered not suitable for revascularization treated conservatively. To have some evidence, we have consulted the literature of the past two decades.

The revascularization rate has significantly fluctuated from 80%, in some single-center study with a more aggressive approach,[30],[31],[32] to lower than 60% showed in some multicenter trials.[33],[34],[35],[36] representing the average of CLI patient conservative care likely.

Moreover, in 2013, in a Medicare population data study, Baser reported that, in the United States, revascularization was offered only to 34% of CLI patients at their first episode. He concluded that it was reasonable to guess that more than 50% of patients were provided with medical treatment in real life.[37]

Biancari, in 2014, in 2144 legs with CLI, reported a 20% rate of conservative treatment.[26]

Moreover, in 2018, analyzing the CLI treatment from 1993 to 2015, our previous review showed that 18% of 5000 patients at their first episode were still conservatively treated.

Simultaneously, the revascularization grew from 50% to 72%, and more significantly, the endovascular procedures from 2% to 77%.[38]

Therefore, from these data, it is reasonable to guess that about 20% of CLI patients are still treated with medical therapy because considered not suitable for revascularization. , Hence, almost one in five of the total CLI population.

Clinical features of patients with critical limb ischemia not suitable for revascularization

Patients with CLI present a broad spectrum of clinical signs, hemodynamic conditions, and anatomic diseases. These patients have high comorbidity and a very high risk of limb amputation and mortality.[6] Data from the literature show that 23% required major amputation after 2 years, and 31.6% had died, primarily of cardiovascular disease.[39]

In these patients, the age-adjusted prevalence of diabetes, ischemic stroke, heart failure, and atrial fibrillation is doubled and tripled in renal failure. One in five has a cancer diagnosis.[40] However, other conditions such as the patients with no prospect of mobilization, limited life expectancy, or failing to consent to an invasive treatment have been reported. Furthermore, the TASC II C/D lesions have been among the criteria of choice for conservative treatment.[41],[42]

The most frequent motivations for conservative treatment are the high comorbidity associated with poor leg pedal arterial run-off with a not limb or life-threatening skin lesion.[34],[39]

Treatments for critical limb ischemia not suitable for revascularization over the past 20 years

Over the past two decades, the guidelines on PAD suggested performing conservative treatment for patients with CLI not suitable for revascularization, with the best medical therapy for atherosclerosis risk factors, comorbidities, pain and wounds.[1],[3],[4],[5],[7],[10],[21],[22],[23],[24],[25]

Other treatments such as prostanoids,[8],[9],[10],[11] vasodilators,[1],[3],[10] heparin,[43] spinal cord stimulation,[12] hyperbaric oxygen therapy,[1],[7] intermittent pneumatic compression,[13],[14],[15],[16],[17] and more recently, angiogenic therapies have raised some concerns about their use to improve the patients' outcomes.[18],[19],[20]

The efficacy of all these treatments has been discussed in the literature causing controversial debate not always in agreement over the past two decades, as reported in [Table 1].
Table 1: Evidenceinguidelinefrom2000to2020;ofprostanoids,vasoactivedrugs,hyperbaricoxygentherapy,spinalcordstimulation,intermittentpneumaticcompression,angiogenictreatments

Click here to view

The use of prostanoids has been one of the most argued issues.

Prostanoids are a group of molecules inhibiting the activation and adhesion of platelets and leukocytes. This family includes prostaglandin E1 (PGE 1), prostacyclin (PGI 2), epoprostenol (PG12), lipo-ecraprost, taprostene, and iloprost.

These drugs promote vasodilation and vascular endothelial cytoprotection through antithrombotic and profibrinolytic actions, which are deemed favorable for CLI.[8],[9],[10],[11]

After the enthusiastic results in the '90s,[8],[9] concerns about their effectiveness on CLI have been raised in the years later.[44] Consequently, the guidelines have weakened the level of their recommendations and in some cases, have defined them as ineffective.[7]

However, recently, some new observations have highlighted a possible role of prostanoids in CLI again.

In 2012, our previous retrospective observation in 99 elderly patients with not reconstructable CLI, 88% received prostanoids infusions, 14% low-molecular-weight heparin or oral anticoagulants, 3% spinal cord stimulation, 17% hyperbaric oxygen therapy, and 69% wound treatment. At 24 months, 13% of patients underwent toe or other foot-sparing amputations, 9.3% had a major amputation, and 23.2% died.[45]

Vietto et al., in a 2018 Cochrane review, found that prostanoids reduced rest pain and promoted ulcer healing in CLI patients with moderate-quality evidence.[46]

The global vascular and European Society of Vascular Medicine guidelines in 2019 have suggested their use again, albeit in selected CLI patients not suitable for revascularization.[4],[5]

Meini et al. in 2020 reported that the coarse efficacy claimed about prostanoids in the past was achieved by analyzing the whole group of prostanoids. Iloprost alone has shown results in reducing pain and improving wound healing in CLI.[47]

Nevertheless, besides these new observations about a revival of prostanoids in CLI, recent reviews have shown a generally better outcome of the conservative treatment in CLI over the past decade. Van Reijen et al. this year observed a 12-month major amputation rate between 22% and 27% and a mortality of 18%–22%.[27] According to these authors, these better outcomes might be due to cardiovascular risk management in the past 20 years and in particular, by more aggressive statin therapy in PAD, as some other authors reported.[27],[48],[49]

Indeed, the heart protection study published in 2002 showed the positive effects of blood lipid-lowering on PAD patients. This study showed that 40 mg daily of simvastatin reduced 25% of the cardiovascular events, suggesting that statin therapy reduced the inflammation burden of patients with PAD.[50]

Years later, the JUPITER study confirmed this suggestion, revealing that rosuvastatin 20 mg daily reduce up to 54% of the incidence of myocardial infarctions, to 48% the strokes and 46% the arterial revascularization in those patients with a low or high level of low-density lipoprotein (LDL) cholesterol but with a high level of protein C.[51]

The following study reinforced the concept demonstrating reduced major amputation and mortality rates among patients with stable PAD receiving high-dose statins.[48]

Now, statin treatment is recommended by the most recent international guideline for all PAD patients with a recommendation I A[4],[5]

Moreover, the positive statin effects on PAD outcomes also, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), have shown a beneficial effect in reducing limb amputation rates.[52]

ACE and ARBs are well known to reduce the risk of cardiovascular major events and mortality in patients with PAD.

Khan et al. recently reported that these drugs had significantly improved limb survival and amputation-free survival in CLI at 5 years, reaching 88% and 77.3%, respectively.[52]

Besides the positive outcomes on the cardiovascular system by lowering blood pressure, ACE and ARBs inhibitors have a pleiotropic protective action on arterial vessels.

In particular, they stabilize the atherosclerotic plaques, improve endothelial function, and enhance angiogenesis. These effects seem to be of specific interest for microcirculation and consequently, might determine the limb's fate in CLI patients.[53]

Therefore, the reported observations highlighting the recent reduction of amputations and mortality observed in CLI patients treated conservatively might have been achieved with more aggressive management of cardiovascular risk factors than other treatments.

New treatments for critical limb ischemia?

Besides the recent reassessment of the use of prostanoids to reduce pain and improve healing of skin ulcerations in CLI, the above suggested recent observations may indicate new strategies of treatment for CLI.

The further cardiovascular outcomes research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) study showed that evolocumab, a PCSK9 inhibitor reduced major cardiovascular events by 27% and in particular, the acute limb ischemia by 44%, and limb amputation of 70% in PAD patients already receiving statin therapy.[29]

The data coming from the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) study showed that, in PAD patients treated with low-dose rivaroxaban plus aspirin, the cardiovascular death, myocardial infarction, or stroke was reduced by 30% less than aspirin alone, major adverse limb events were also reduced by 55% and major amputations alone by 70%.[28],[54]

The vascular outcome study of ASA and rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD) study[51] confirmed the favorable outcomes of the COMPASS study. This study found a reduction of 20% in coronary heart disease death, myocardial infarction, ischemic stroke, and acute limb ischemia.[55]

The results provided by the FOURIER, COMPASS, and VOYAGER PAD studies have not yet been tested on CLI patients and in particular, on those deemed not suitable for revascularization.

However, they provide many arguments to presume positive effects in these patients more affected by inflammation or conditions that may lead to atherothrombosis.

The reduction of LDL-cholesterol associated with better control of the atherothrombotic process with low-dose rivaroxaban plus aspirin could reduce the risk of adverse cardiovascular and limb events in CLI patients not suitable for arterial reopening procedures.[28],[55]

Consequently, despite the higher major bleeding expected,[54],[55],[56] these new treatments could represent an absolute novelty for CLI in terms of net clinical benefit.

Final comment

This work highlights how in the past 20 years, PAD guidelines have not considered the CLI patients not suitable for revascularization. However, despite the progress of revascularization techniques, their percentage has remained high. About 20% of the entire CLI patient population is treated with conservative therapy in their first episode, even today.

These patients with CLI not suitable for revascularization remain neglected by the literature that seems more committed to following the progress of revascularization techniques.

This discrepancy highlights an awareness problem that affects the entire population of CLI patients.

Even today, recent observations confirm the disparities in PAD awareness in European countries.[56] Reduced awareness in the PAD is an old and severe problem, but it becomes more so in the CLI.

Although the PARTNERS study in 2001 underlined the lack of early diagnosis of PAD,[57] Goodney, in 2013, observed that many patients do not even receive angiography in the year before major limb amputation.[58] About 50% of patients presenting with CLI have no previous PAD diagnosis.[59],[60] All these data suggest that an unknown PAD could often lead to limb amputation after skin not healing posttraumatic ulcers in an elderly asymptomatic patient.

Early diagnosis of CLI becomes then essential for a good outcome.[61]

Another aspect that limits the understanding of the treatment efficacy used for patients with not revascularizable CLI is the outcome assessment.

CLI patients not suitable for revascularization may be need focused outcomes and in particular, those patients conservatively treated. Their outcomes should be related to their real-life expectancy than to the amputation or mortality rates reported in many studies regarding not frail CLI patients.

Many of these patients treated conservatively have limited deambulatory capacity and expectancy of life, and sometimes, the relief of pain could significantly improve their quality of life.

In conclusion, the literature should increase attention to not revascularizable patients to improve its incomplete CLI picture. Improve treatment and address unmet needs could benefit this vulnerable population.[62]

We can finally underline the compelling need to improve CLI patients' knowledge not suitable for revascularization to enhance the understanding of CLI.

However, these patients remain neglected by literature, orphan of specific management, and still resident in the dark side of the CLI.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45 Suppl S:S5-67.  Back to cited text no. 1
Caimi G, Canino B, Lo Presti R, Urso C, Hopps E. Clinical conditions responsible for hyperviscosity and skin ulcers complications. Clin Hemorheol Microcirc 2017;67:25-34.  Back to cited text no. 2
Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): A collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463-654.  Back to cited text no. 3
Conte MS, Bradbury AW, Kolh P, White J V, Dick F, Fitridge R, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg 2019;69 6 Suppl: 3S-125S.e40.  Back to cited text no. 4
Frank U, Nikol S, Belch J, Boc V, Brodmann M, Carpentier PH, et al. ESVM Guideline on peripheral arterial disease. Vasa 2019;48:1-79.  Back to cited text no. 5
Abu Dabrh AM, Steffen MW, Undavalli C, Asi N, Wang Z, Elamin MB, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg 2015;62:1642- 51.e3.  Back to cited text no. 6
Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017;135:e726-9.  Back to cited text no. 7
Diehm C, Abri O, Baitsch G, Bechara G, Beck K, Breddin HK, et al. Iloprost, a stable prostacyclin derivative, in the treatment of stage IV arterial disease: A placebo-controlled multicentre trial. Dtsch Med Wochenschr 1989;114:783-8.  Back to cited text no. 8
Treatment of limb threatening ischaemia with intravenous iloprost: A randomised double-blind placebo controlled study. U.K. Severe Limb Ischaemia Study Group. Eur J Vasc Surg 1991;5:511-6.  Back to cited text no. 9
Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31:S1-296.  Back to cited text no. 10
Norgren L, Alwmark A, Angqvist KA, Hedberg B, Bergqvist D, Takolander R, et al. A stable prostacyclin analogue (iloprost) in the treatment of ischaemic ulcers of the lower limb. A Scandinavian-Polish placebo controlled, randomised multicenter study. Eur J Vasc Surg 1990;4:463-7.  Back to cited text no. 11
Spincemaille GH, de Vet HC, Ubbink DT, Jacobs MJ. The results of spinal cord stimulation in critical limb ischaemia: A review. Eur J Vasc Endovasc Surg 2001;21:99-105.  Back to cited text no. 12
van Bemmelen PS, Mattos MA, Faught WE, Mansour MA, Barkmeier LD, Hodgson KJ, et al. Augmentation of blood flow in limbs with occlusive arterial disease by intermittent calf compression. J Vasc Surg 1994;19:1052-8.  Back to cited text no. 13
van Bemmelen PS, Weiss-Olmanni J, Ricotta JJ. Rapid intermittent compression increases skin circulation in chronically ischemic legs with infra-popliteal arterial obstruction. Vasa 2000;29:47-52.  Back to cited text no. 14
van Bemmelen PS, Gitlitz DB, Faruqi RM, Weiss-Olmanni J, Brunetti VA, Giron F, et al. Limb salvage using high-pressure intermittent compression arterial assist device in cases unsuitable for surgical revascularization. Arch Surg 2001;136:1280-5.  Back to cited text no. 15
Louridas G, Saadia R, Spelay J, Abdoh A, Weighell W, Arneja AS, et al. The Art Assist Device in chronic lower limb ischemia. A pilot study. Int Angiol 2002;21:28-35.  Back to cited text no. 16
Sultan S, Hamada N, Soylu E, Fahy A, Hynes N, Tawfick W. Sequential compression biomechanical device in patients with critical limb ischemia and nonreconstructible peripheral vascular disease. J Vasc Surg 2011;54:440-6.  Back to cited text no. 17
Nikol S, Baumgartner I, Van Belle E, Diehm C, Visoná A, Capogrossi MC, et al. Investigators. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 2008;16:972-8.  Back to cited text no. 18
Benoit E, O'Donnell TF Jr., Iafrati MD, Asher E, Bandyk DF, Hallett JW, et al. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: Implications for clinical trial design. J Transl Med 2011;9:165.  Back to cited text no. 19
Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT, et al. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: The randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther 2012;20:1280-6.  Back to cited text no. 20
Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery. J Vasc Surg 2011;54:e32-58.  Back to cited text no. 21
Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clément D, Collet JP, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: The Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2851 906.  Back to cited text no. 22
Setacci C, de Donato G, Teraa M, Moll FL, Ricco JB, Becker F, et al. Chapter IV: Treatment of critical limb ischaemia. Eur J Vasc Endovasc Surg 2011;42 Suppl 2:S43-59.  Back to cited text no. 23
Guyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141 2 Suppl: 53S-70S.  Back to cited text no. 24
Aboyans V, Ricco JB, Bartelink ME, Björck M, Brodmann M, Cohnert T, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur Heart J 2018;39:763-816.  Back to cited text no. 25
Biancari F. Meta-analysis of the prevalence, incidence and natural history of critical limb ischemia. J Cardiovasc Surg (Torino) 2013;54:663-9.  Back to cited text no. 26
van Reijen NS, Hensing T, Santema TKB, Ubbink DT, Koelemay MJ. Outcomes of Conservative Treatment in Patients with Chronic Limb Threatening Ischaemia: A Systematic Review and Meta Analysis. Eur J Vasc Endovasc Surg 2021;S1078-5884(21)00048-4. [doi: 10.1016/j.ejvs.2021.01.005].  Back to cited text no. 27
Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: An international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219-29.  Back to cited text no. 28
Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: Insights from the FOURIER trial (further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk). Circulation 2018;137:338-50.  Back to cited text no. 29
Holdsworth J. District hospital management and outcome of critical lower limb ischaemia: Comparison with national figures. Eur J Vasc Endovasc Surg 1997;13:159-63.  Back to cited text no. 30
Shah AP, Klein AJ, Sterrett A, Messenger JC, Albert S, Nehler MR, et al. Clinical outcome using aggressive approach to anatomic screening and endovascular revascularization in a Veterans Affairs population with critical limb ischemia. Catheter Cardiovasc Interv 2009;74:11-9.  Back to cited text no. 31
Bisdas T, Borowski M, Torsello G, First-Line Treatments in Patients With Critical Limb Ischemia (CRITISCH) Collaborators. Current practice of first-line treatment strategies in patients with critical limb ischemia. J Vasc Surg 2015;62:965-73.e3.  Back to cited text no. 32
Critical limb ischaemia: Management and outcome. Report of a national survey. The Vascular Surgical Society of Great Britain and Ireland. Eur J Vasc Endovasc Surg 1995;10:108-13.  Back to cited text no. 33
Lepäntalo M, Mätzke S. Outcome of unreconstructed chronic critical leg ischaemia. Eur J Vasc Endovasc Surg 1996;11:153-7.  Back to cited text no. 34
Bailey CM, Saha S, Magee TR, Galland RB. A 1 year prospective study of management and outcome of patients presenting with critical lower limb ischaemia. Eur J Vasc Endovasc Surg 2003;25:131-4.  Back to cited text no. 35
Awad S, Karkos CD, Serrachino-Inglott F, Cooper NJ, Butterfield JS, Ashleigh R, et al. The impact of diabetes on current revascularisation practice and clinical outcome in patients with critical lower limb ischaemia. Eur J Vasc Endovasc Surg 2006;32:51-9.  Back to cited text no. 36
Baser O, Verpillat P, Gabriel S, Wang L. Prevalence, incidence, and outcomes of critical limb ischemia in the US Medicare population. Vasc Dis Manag 2013;10:26-36.  Back to cited text no. 37
Martini R. Trends of the treatment of Critical Limb Ischemia during the last two decades. Clin Hemorheol Microcirc 2018;69:447-56.  Back to cited text no. 38
Marston WA, Davies SW, Armstrong B, Farber MA, Mendes RC, Fulton JJ, et al. Natural history of limbs with arterial insufficiency and chronic ulceration treated without revascularization. J Vasc Surg 2006;44:108-14.  Back to cited text no. 39
Baubeta Fridh E, Andersson M, Thuresson M, Sigvant B, Kragsterman B, Johansson S, et al. Amputation Rates, Mortality, and Pre-operative Comorbidities in Patients Revascularised for Intermittent Claudication or Critical Limb Ischaemia: A Population Based Study. Eur J Vasc Endovasc Surg 2017;54:480-6.  Back to cited text no. 40
Martini R. Current opinions about the definition of critical limb ischemia: A debate still open after three decades. Clin Hemorheol Microcirc 2019;73:341-6.  Back to cited text no. 41
Stavroulakis K, Borowski M, Torsello G, Bisdas T, CRITISCH Collaborators. One-Year Results of First-Line Treatment Strategies in Patients With Critical Limb Ischemia (CRITISCH Registry). J Endovasc Ther 2018;25:320-9.  Back to cited text no. 42
Andreozzi GM, Signorelli SS, Cacciaguerra G, Di Pino L, Martini R, Monaco S, et al. Three-month therapy with calcium-heparin in comparison with ticlopidine in patients with peripheral arterial occlusive disease at Leriche-Fontaine IIb class. Angiology 1993;44:307-13.  Back to cited text no. 43
Ruffolo AJ, Romano M, Ciapponi A. Prostanoids for critical limb ischemia. Cochrane Database Syst Rev 2007;2: 1465-1858. [doi: 10.1002/14651858.CD006544].  Back to cited text no. 44
Martini R, Andreozzi GM, Deri A, Cordova R, Zulian P, Scarpazza O, et al. Amputation rate and mortality in elderly patients with critical limb ischemia not suitable for revascularization. Aging Clin Exp Res 2012;24 3 Suppl: 24-7.  Back to cited text no. 45
Vietto V, Franco JV, Saenz V, Cytryn D, Chas J, Ciapponi A. Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev 2018;1:CD006544.  Back to cited text no. 46
Meini S, Dentali F, Melillo E, de Donato G, Mumoli N, Mazzone A. Prostanoids for critical limb ischemia: A clinical review and consideration of current guideline recommendations. Angiology 2020;71:226-34.  Back to cited text no. 47
Arya S, Khakharia A, Binney ZO, DeMartino RR, Brewster LP, Goodney PP, et al. Association of statin dose with amputation and survival in patients with peripheral artery disease. Circulation 2018;137:1435-46.  Back to cited text no. 48
Armstrong EJ, Chen DC, Westin GG, Singh S, McCoach CE, Bang H, et al. Adherence to guideline-recommended therapy is associated with decreased major adverse cardiovascular events and major adverse limb events among patients with peripheral arterial disease. J Am Heart Assoc 2014;3:e000697.  Back to cited text no. 49
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7-22.  Back to cited text no. 50
Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER). Am J Cardiol 2010;106:204-9.  Back to cited text no. 51
Khan SZ, O'Brien-Irr MS, Rivero M, Blochle R, Cherr GS, Dryjski ML, et al. Improved survival with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic limb-threatening ischemia. J Vasc Surg 2020;72:2130-8.  Back to cited text no. 52
Shahin Y, Khan JA, Samuel N, Chetter I. Angiotensin converting enzyme inhibitors effect on endothelial dysfunction: A meta-analysis of randomised controlled trials. Atherosclerosis 2011;216:7-16.  Back to cited text no. 53
Anand SS, Eikelboom JW, Dyal L, Bosch J, Neumann C, Widimsky P, et al. Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS trial. J Am Coll Cardiol 2019;73:3271-80.  Back to cited text no. 54
Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR,Patel MR, et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med 2020;382:1994 2004.  Back to cited text no. 55
Bauersachs R, Brodmann M, Clark C, Debus S, De Carlo M, Gomez Cerezo JF, et al. International public awareness of peripheral artery disease. Vasa 2021;0:1 7. [doi: 10.1024/0301-1526/a000945].  Back to cited text no. 56
Hirsch AT, Hiatt WR, PARTNERS Steering Committee. PAD awareness, risk, and treatment: New resources for survival – The USA PARTNERS program. Vasc Med 2001;6:9-12.  Back to cited text no. 57
Goodney PP, Holman K, Henke P, Travis L, Dimick JB, Stukel TA, et al. Regional intensity of vascular care and lower extremity amputation rates. J Vasc Surg 2013;57:1471 80.  Back to cited text no. 58
Nehler MR, Hiatt WR, Taylor LM Jr. Is revascularization and limb salvage always the best treatment for critical limb ischemia? J Vasc Surg 2003;37:704-8.  Back to cited text no. 59
Nehler MR, McDermott MM, Treat-Jacobson D, Chetter I, Regensteiner JG. Functional outcomes and quality of life in peripheral arterial disease: Current status. Vasc Med 2003;8:115-26.  Back to cited text no. 60
Reinecke H, Unrath M, Freisinger E, Bunzemeier H, Meyborg M, Lüders F, et al. Peripheral arterial disease and critical limb ischaemia: Still poor outcomes and lack of guideline adherence. Eur Heart J 2015;36:932 8.  Back to cited text no. 61
Creager MA. A Bon VOYAGER for peripheral artery disease. N Engl J Med 2020;382:2047-8.  Back to cited text no. 62


  [Table 1]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Article Tables

 Article Access Statistics
    PDF Downloaded58    
    Comments [Add]    

Recommend this journal